SAN DIEGO -- An antigen-based immunotherapy has failed to halt the progression of type 1 diabetes after one year, researchers reported here.

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Explain that an antigen-based immunotherapy using injections of glutamic acid decarboxylase (GAD) has failed to halt the progression of type 1 diabetes after one year.

Note that there were no differences in adverse events, and the treatment was generally well-tolerated.

SAN DIEGO -- An antigen-based immunotherapy has failed to halt the progression of type 1 diabetes after one year, researchers reported here.

At one year, there were no differences in beta cell function, as measured by C-peptide levels, among recently diagnosed patients who had injections of glutamic acid decarboxylase (GAD) or placebo, Diane Wherrett, MD, of the Hospital for Sick Children in Toronto, and colleagues reported at the American Diabetes Association meeting and simultaneously online in The Lancet.

"Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge," they wrote.

Jay Skyler, MD, of the University of Miami, a co-author of the study, said during an ADA press briefing that the "curves were superimposable for one year of follow-up, showing no effects whatsoever. But there were no side effects either."

There have been many trials of monoclonal antibodies and immunosuppressive drugs in preventing progression of type 1 disease, but since these up the risk of generalized immunosuppression, a more specific approach may be desirable, Wherrett and colleagues wrote.

One such approach could be to interfere with the interaction between pathogenic T cells and their target antigens, they said. For instance, GAD is a major target of the autoimmune response in type 1 diabetes, and previous models have shown that giving GAD to diabetic mice prevents disease progression.

So to assess whether immunization with GAD -- combined with an adjuvant of aluminum hydroxide (GAD-alum) -- would preserve insulin production in recent-onset type 1 diabetes, the researchers enrolled 145 patients, ages 3 to 45, who were newly diagnosed (less than 100 days before enrollment) with type 1 disease at 15 sites in the U.S. and Canada.

Patients received one of three treatments:

Three injections of 20 µg GAD-alum (GAD-alum group)

Two injections of 20 µg GAD-alum and one of alum (GAD-alum plus aluminum group)

Three injections of aluminum hydroxide (aluminum-only group)

The vaccine was given at baseline, four weeks later, and eight weeks after the second injection.

The primary outcome was the adjusted mean area under the curve (AUC) of serum C-peptide during the first two hours of a four-hour mixed meal tolerance test at one year. Secondary outcomes included changes in HbA1c and insulin dose.

Wherrett and colleagues found that at one year, C-peptide levels were similar across groups: 0.412 nmol/L in the GAD-alum group, 0.382 in GAD-alum plus aluminum, and 0.413 in the aluminum-only group.

HbA1c and insulin dose increased gradually over time and were similar across groups at one year, the researchers reported. There were no differences in adverse events, and the treatment was generally well-tolerated.

They noted that GAD antibody titers rose in the GAD-alum groups in response to immunizations, showing that an immune response did indeed occur.

"The lack of efficacy of antigen-based therapy in our study is disappointing, but is in keeping with similar results in other autoimmune disorders, such as rheumatoid arthritis and multiple sclerosis," they said.

They added that GAD treatment even earlier in disease could be effective. Skyler said during the briefing that combining antigen immunotherapy with immunosuppressive agents, such as anti-CD3 antibodies, may be the way forward.

He also noted that a second trial of GAD vaccination presented at the meeting by Johnny Ludvigsson, MD, PhD, of Linköping University in Sweden, and colleagues also failed to show beneficial effects, which contrasted with their earlier findings.

In an accompanying editorial in The Lancet, Chantal Mathieu, MD, and Pieter Gillard, MD, of University Hospital Leuven in Belgium, wrote that with such negative results, the "inclination might be to abandon hope" for preventing and treating type 1 diabetes.

But the findings are "an important step in research toward future interventions," the editorialists wrote, particularly because Wherrett's group set an example for how concepts should be tested. Their work is done through Type 1 Diabetes TrialNet, which enables rapid enrollment and results.

"The machinery exists to do the trials, as do the ideas and motivation," Matthieu and Gillard wrote. "What is needed is the continued interest of agencies, pharmaceutical companies, and the scientific community in the quest to beat this disease."

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